Leishmania are typanosomatid protozoans that are transmitted by phlebotomine sand flies causing leishmaniasis. Leishmaniasis affects 12 million people in 88 countries with an estimated 350 million people that are at risk of infection by the different species of Leishmania. The annual incidence of new cases is about 2 million. Like many other tropical diseases, the leishmaniases are related to economic development and man-made environmental changes, which increase exposure to the sandfly vector. The disease has assumed importance for the United States as many soldiers serving in Iraq and Afghanistan veterans are exposed to sand flies and are afflicted with leishmaniasis. Leishmania/HIV coinfection is emerging as an extremely serious, new disease and it is increasing in frequency. Treatment is based primarily on pentavalent antimony compounds although a new drug, miltefosine, shows promise in treating leishmaniasis. Unfortunately, the antimony compounds are toxic and resistance in various endemic regions is common. Miltefosine has only been recently approved in India and its effectiveness in the field and the development of resistance are unknown. However, experience with antibiotics, including antibacterials, antifungals, and antivirals, indicates that resistance to currently-used drugs is the rule rather than the exception; this necessitates the continued search for new drugs. Particularly useful and missing from the armamentarium of treatment is prevention by an efficacious and safe pan-Leishmania vaccine. Our long-term goal is the identification and development of vaccines for the prevention or treatment of a number of human infectious diseases, including those caused by Leishmania. In this SBIR Phase I, we will test the efficacy of several putative antigens, delivered in a novel way, in protecting against infection by L. major. We will accomplish this in two specific aims: Aim One: Engineer yeast cells to express each of four candidate proteins using recombinant DNA technology. Aim Two: Test the in vivo efficacy of each vaccine formulation to protect vaccinated animals against a challenge of L. major. [unreadable] This work will be a prelude to further work in Phase II that will include testing for in vivo efficacy of each successful vaccine candidate in several Leishmania infection models as well as the detailed understanding of the immune response of each formulation. We believe that this work will lead to the development of prophylactic and therapeutic vaccines against Leishmania [unreadable] [unreadable]